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It’s one of the more puzzling observations in medicine: The vast majority of chronic pain patients are women. Women suffer disproportionately from irritable bowel syndrome, fibromyalgia, headaches (especially migraines), pain caused by damage to the nervous system, osteoarthritis, jaw problems like TMJ, and much more. Women also report more acute pain than men after the same common surgeries.

In the lab, when researchers ask male and female volunteers to subject themselves to experimental pain — increasingly hot stimulation on the inner arm, immersion of the hand in very cold water, electrical jolts to the skin — women show lower pain thresholds (that is, they report pain at lower levels of stimulus intensity) and lower tolerance (they can’t bear intense pain as long).

Women are also better able to detect small gradations in pain stimuli. And they respond differently to certain opioid — painkilling — drugs. (It’s not clear whether men and women differ in sensitivity to cancer pain.)

But it’s only recently that researchers have begun to study the exact genetic, physiological, hormonal, and psycho-social factors that may underlie these sex differences. In part, that’s because pain researchers have been hampered by one — rather shocking — fact: Most basic pain research is still done in male mice and rats.

This has been “a catastrophe,’’ says McGill University pain geneticist Jeffrey Mogil, adding that the old rationale that menstrual cycles make females too difficult to study is bogus. Men and women, in fact, can be so different in the way their nervous systems process pain that someday there may be “pink pills for women, and blue pills for men,’’ he says. The lopsided research exists solely because of “inertia,’’ he adds.

Others agree, among them Dr. Roger B. Fillingim, lead author of an exhaustive 2009 review of sex and pain research published by the American Pain Society. In that paper, Fillingim, a pain researcher at the University of Florida, notes that while the National Institutes of Health now require routine inclusion of both sexes in human studies, much animal research “continues to eschew females.’’ Given that pain is mainly a female problem, he adds, this means research “that excludes females is incomplete at best and invalid at worst.’’

Luckily, this shutout is not total, and of course, some human research does specifically address sex differences — with complex, and fascinating results.

Take hormones. Growing up, boys and girls show comparable patterns of pain until puberty, notes Dr. Navil Sethna, a pediatric anesthesiologist at Children’s Hospital Boston. “After puberty, certain types of pain are more common in girls, and even if the incidence is the same, reported pain severity is more intense in girls than boys, especially for headaches and abdominal pain,’’ says Sethna. This pattern persists through adulthood; the lifetime prevalence for migraines is 18 percent for women and 6 percent for men.

The same pattern holds for TMJ, temporomandibular joint disease — now called TMD — with no sex differences before puberty and significant differences afterward.

Not all studies agree, but many do show that after puberty, women experience striking fluctuations in their response to pain at different points in the menstrual cycle. This has been noted in irritable bowel syndrome, TMD, headache, and fibromyalgia. One explanation, some researchers say, is that estrogen protects against pain at high levels, and enhances it at low levels. (The male hormone testosterone seems to protect against pain.)

This theory fits with the observation that during pregnancy, when estrogen levels are high, women often get fewer migraines and TMD pain. And it fits withthe observation that, after childbirth, when estrogen falls abruptly, the number of migraine attacks increases.

It may not be the absolute level of estrogen that is key, says Dr. Fernando Cervero, a pain researcher at McGill, but the fluctuations in hormonal levels during the menstrual cycle. (Estrogen levels climb in the first half of the cycle, then decline in the second half.) “It’s the change that produces the change’’ in perceptions of pain, he says.

What about that big hormonal change, menopause? That’s when estrogen falls abruptly. If the low estrogen-more pain theory is true, women should experience more pain after menopause, but research results are all over the place.

Several studies have shown that women who combat low levels of estrogen by taking hormone replacement therapy actually have more back pain and more pain from TMD as well. Other studies detect no link between hormone replacement therapy and pain in older women. And still others show that when women stop taking hormone replacement therapy, their pain appears to go up and they may get more migraines.

Females “may have evolved sensory mechanisms that allow for greater acuity across sense organs’’ over the eons, says Dr. William Maixner, director of the Center for Neurosensory Disorders at the University of North Carolina, Chapel Hill. Females are more sensitive in general to changes in smell, temperature, visual cues, and other stimuli that may signal danger — traits that could have helped them in earlier times to protect the children they watched while the men were away. Experiencing pain in a more heightened way may be one more example of that sensitivity.

“The conditions that cause pain affect men and women differently in terms of prevalence and severity,’’ notes Dr. Daniel Carr, a professor of pain research at Tufts Medical Center. Some drugs also affect men and women differently. And then there’s “the whole social dimension and cultural dimension of being a woman versus being a man, which modifies’’ treatment choices. In other words, he says, “Whatever pain therapy one selects should have some flexibility to it.’’

One thing is clear: In this culture, women are often encouraged to express pain, and men to hide it. But this doesn’t mean that friends, relatives — and doctors — react sympathetically to women’s expression of pain. In the clinic, this often translates to gender bias and under-treatment of pain, notes Fillingim.

Women, he says, should not put up with any doctor who says or implies that “you are just another whining woman.’’ But neither, he adds, should men stick with doctors who don’t respect them or believe their pain.

“There are doctors with a greater understanding of pain in general and a greater willingness to deal with it, and others who, if they can’t see it on an X-ray, don’t believe it’s real,’’ Fillingim adds. Bottom line? “Avoid that latter category.’’

This is Judy Foreman’s last Health Sense column for a while. She is writing a book on chronic pain, provisionally titled “A Nation in Pain: Treating Our Biggest Health Problem.’’ She invites readers to send their personal stories of pain to judyforeman@myhealthsense.com.

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One tiny piece of the pain puzzle illustrates just how complex the interplay among sex, genetics, and response to medications can be.

In 2003, Jeffrey Mogil, a pain geneticist who studies rodents at McGill University, and Roger Fillingim, a psychologist and human pain researcher at the University of Florida, joined forces to test a prediction of Mogil’s: That redheaded women, but not men (redheaded or otherwise) would respond especially well to the pain-reliever drug pentazocine, or Talwin.

Researchers already knew that there are significant sex differences in responsiveness to opioid drugs, or narcotics, in both mice and people. For both, certain opioid receptors in the nervous system act like magnets to pain-reducing opioids, whether pumped out naturally by the body or taken as drugs.

Using fancy genetic mapping, Mogil, the mouse guy, and Fillingim, the people person, found that one particular receptor gene called Mc1R may hold the key to part of the differences in pain processing.

Women (and mice) with red hair (actually yellowish in mice) or very fair skin typically have two mutant copies of this gene (one from each parent), rendering them useless. The redheaded women experienced “significantly greater analgesia,’’ that is, pain relief, from pentazocine than any of the other test groups, Mogil and Fillingim concluded in their Proceedings of the National Academy of Sciences paper.

At a recent conference on pain in Montreal, Mogil’s team showed that another receptor important for pain processing, TLR4, plays no role at all in controlling pain in female mice, though it does in males.

So, go figure. At the moment, the intricacies of genetics, sex, and pain processing are very much a science in its infancy. JUDY FOREMAN

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